Oxygen is supplied to the cells by the blood and most cellular energy production is tightly coupled to oxygen. Whenever the blood flow to an organ is interrupted, a state of ischemia exists. During ischemia, cellular ATP will be consumed and usually cannot adequately be replenished in the absence of a supply of oxygen. Ischemia can exist for only a portion of an organ when the blockage of the blood supply to the organ is not total. In addition to total ischemia, or no blood flow, there are intermediate degrees of ischemia.
Significant ischemia occurs in stroke and during most cases of open heart surgery, all episodes of coronary occlusion or heart attack, all cases of organ transplantation, certain procedures such as liver shunt operations and a variety of other situations in which either significant stress or a period of shock has compromised the functioning of one or more organs of the body. In all of these situations, cellular energy metabolism is impaired, and its restoration is critical to the recovery of organ function.
For example, stroke, or cerebrovascular disease, is the name for several disorders that occur within seconds or minutes after the blood supply to the brain is disturbed. Stroke is the third leading cause of death in developed countries. Approximately 550,000 Americans suffer a stroke each year; one fourth of them die and half of the survivors have residual disabilities, including paralysis of face or extremities, speech disorders, loss of bladder function, inability to swallow or dementia. Stroke is the principal cause of severe disability, often requiring institutionalization of stroke survivors at a total cost in the U.S. of $20 to 30 billion dollars per year. Stroke is more likely to occur in the elderly, and the risk doubles each decade after age 35 years. Five percent of the population older than 65 years has had a stroke.
Symptoms of stroke may progress or fluctuate during the first day or two after onset; this is called evolution. When no further deterioration occurs, the condition is considered to be a completed stroke. The only warning signal that suggests susceptibility to a stroke is a transient ischemic attack (TIA).
Strokes are characterized by the location and type of disturbance. The most common is a deficient supply of blood through an artery (ischemia). About 84% of strokes (about 400,000 per year in the U.S.) result from occlusion of cerebral arteries by blood clots. Ischemic cell damage follows rapidly upon interruption of the blood supply downstream from the clot. The remaining 16% of strokes are the result of intracerebral or subarachnoid hemorrhage. While hemorrhage induces other injurious events, ischemia resulting from the "short circuited" blood flow is still a significant factor in neuronal damage from hemorrhagic strokes.
Cell death occurs rapidly in the core region of a stroke, where blood flow is reduced to about 20% of normal. However, there is a larger area of potential injury, called the ischemic penumbra, where blood flow is reduced to a lesser extent. Cells in this region are endangered, but may not be irreversibly damaged. It is this penumbral area wherein neuroprotective agents may have their most beneficial effects in preventing cell damage and death due to ischemia and thereby reducing the incidence of long term disabilities.
Pharmacological intervention into the stroke process has not been successful. For example, studies evaluating the effectiveness of corticosteroids in the setting of head injury or global or focal brain ischemia have demonstrated either no improvement or a worsening of neurological outcome. See, for example, C. T. Wass et al., Anesthesiology, 84, 644 (1996) and references cited therein. A study of stroke patients treated primarily with dexamethasone or methylprednisolone showed no significant difference in outcome between steroid and non-steroid treated patients. J. DeReuck et al., Eur. Neurol., 28, 70 (1988).
Due to the lack of available pharmacotherapeutic agents, a significant percentage of the population subject to stroke or its after effects are poorly managed. None of the drugs presently available are capable of preventing damage due to stroke and most, such as anticoagulants, which can be shown to speed clot dissolution and hasten reperfusion if given within three hours of the onset of ischemia, have disturbing side effects. Anticoagulants can in fact be fatal if used inappropriately, e.g., for treating a hemorrhagic stroke. Clearly, current therapy has failed to "seize control" of this debilitating pathology.
Therefore, an object of this invention is to provide pharmaceutical agents useful in the treatment of stroke.
A further object of this invention is to provide a method of treating stroke and related ischemic disorders.